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Pathology of Multiple Sclerosis

Demyelinating disorder with inflammation, selective destruction of CNS myelin, and gliosis Can be relapsing or progressive Disseminated in time and space The precise pathogenesis of MS is unknown, but autoimmune contributes There is no specific antigen or antibody. Immunopathology of MS has 2 distinct but overlapping phases 1. Inflammatory Initial stage: Lymphocytes are activated in the periphery by factors such as infection or other metabolic stress. Activated T cells seek entry into the CNS via attachment to a receptor on endothelial cells; Mediated by production of matrix metalloproteinases. Interaction allows a breach in the blood-brain barrier, leading to additional influx of inflammatory cells. Inflammatory cytokines produced cause direct toxicity and also attract macrophages that contribute to demyelination. Macrophages and T-lymphocytes found in increased number in both blood, CSF, and in the lesions 2. Degenerative Reflect axonal degeneration and loss. Demyelination disrupts axonal support and leads to destabilisation of axonal membrane potentials Inflammatory cells, antibodies, and complement may contribute to axonal injury. Characterized by 1. Multifocal areas of demyelination 2. Loss of oligodendrocytes 3. Astrogliosis with loss of axons primarily in the white matter of the CNS. Heterogenous disorder: Mechanisms leading to tissue damage differ from patient to patient. Relapsing-remitting MS (RRMS) shows the most inflammatory activity, followed by relapsing-progressive MS (RPMS) and early secondary-progressive MS (SPMS). Primaryprogressive MS (PPMS) shows a primarily degenerative process. Acute relapses i.e. vision or mobility periods of increased inflammatory activity Clinical progression i.e. gradual loss of ability to ambulate over several years, poorer recovery from relapses, etc.. Manifestation of combined on-going chronic low-level inflammation with degenerative processes.

Activation of macrophages and T lymphocytes and increased immunoglobulin synthesis in both blood and cerebrospinal fluid during the active phase of the disease Management of MS attempts to reduce the potential for relapse and the extent of the relapses. Disease-modifying therapies in MS are most active against inflammation.

Pathological findings Macroscopically: Plaques of demyelination in white matter, perivenular, and widely disseminated Microscopically: Demyelination with tangled masses of preserved axons. Lymphocytic infiltration and astrocytic proliferation seen. No oligodendral cells.

Investigations of Multiple Sclerosis


MRI Help demonstrate presence of multiple lesions

CSF examination Mild lymphocytosis or slightly increased protein concentration (esp after an acute relapse) Elevate IgG and discrete bands of IgG (oligoclonal bands)

Electrophysiological tests Visual-evoked responses (VER) o Delayed VER provide evidence of a optic nerve lesion Somatosensory Evoked Potentials o Delay shows that these pathways have been damaged. Peripheral nerve studies are normal.

Q5: Reaction and prospects


Patients reaction to illness 1) 2) 3) 4) 5) 6) depression anxiety sense of failure Fear of the progressive disabilities Shock I look ok from the outside, but it feels like im having fits on the inside

Important for patient to have social support groups like in Malaysia there is the MS Malaysia: http://www.msmalaysia.com.my/ by UKM

Prospects on disabilities 1) EDSS: Expanded Disability Status Scale: EDSS steps 1.0 to 4.5 refer to people with MS who are able to walk without any aid and is based on measures of impairment in eight functional systems (FS): pyramidal - weakness or difficulty moving limbs cerebellar - ataxia, loss of coordination or tremor brainstem - problems with speech, swallowing and nystagmus sensory - numbness or loss of sensations bowel and bladder function visual function cerebral (or mental) functions 2) Patient to obtain claims: Social Security Claims (SSDI) 3) About 2/3 patients can ambulate for the next 2 decades after diagnosis but most patients are unable to walk when they die. 4) Patients have difficulty swallowing and are at high risk of aspiration pneumonia. 5) Immobility causes patient to get pneumonia as well 6) Eye sight can be affected however rarely they will go completely blind.

Pharmacological agents for multiple sclerosis


Acute relapses Short courses of steroids Sometimes reduce severity. They do not influence long-term outcome.

Preventing relapse and disability Beta-interferon (both INF-1b and 1a) by self-administered injection o Used in RRMS o IFN-1b is also now licensed for SPMS o Reduces relapse rate by 30% in active RRMS o Prevents an increase in lesions seen on MRI. o SE: flu-like symptoms, depression & irritation at injection sites. o Expensive Immunosuppressants & antineoplastic drugs o Trials have sometimes shown slight benefits o E.g. Azathioprine May be as effective as interferon for RRMS 20x cheaper Cyclophosphamide Mitoxantrone Helps SPMS Glatiramer acetate o Immunomodulator o Has been shown to reduce relapse frequency in ambulatory patients with RRMS o Similar to beta-interferon (efficacy) Fingolimoid o Immunomodulator o Sphingosine-1-phosphate (S1P) inhibitor o Prevent lymphocyte from moving to CNS for auto-immune responses o Reduces attack rate o Significantly improves all measures of disease severity in MS Natalizumab o Monoclonal antibody o Inhibits migration of leucocytes into CNS by inhibitory -4 integrins found on the surface of lymphocytes and monocytes. o Useful in severe RRMS that is unresponsive to other treatments. o SE: risk of progressive multifocal leucoencephalopathy (PML)

Community support
Aims and Objectives To promote dissemination of knowledge concerning MS through lectures, exhibitions for professional groups and general public and any other form that can obtain such an objective To establish a register for people with MS in Malaysia To provide information and advice to those with MS or giving care to MS sufferers, through fostering support groups, organizing holiday camps, workshops and other allied activities To approach organizations and individuals in fund raising activities that will go towards activities that reduce the burden of the disease on the patients life To lobby for governmental support in funding treatment in the form of subsidies. To carry out charitable activities for members and the Malaysian community at large. To purchase/lease/lend and other movable / immovable property to further the aims of the Society with the approval of the Registrar of Society and the committee members. In other words: a) Provide support network b) Increase public awareness c) To seek government assistance for those who cant afford to incur the cost every month. Information on their website Working my way through fatigue and stress Understanding my symptoms help me cope better What is MS? What causes MS? Treating Relapsing MS Diagnosing MS Managing your MS A balanced diet works wonders Regular excersice makes me stronger Dealing with constipation, fatigue and stress Adjusting my sexual life around my symptoms There is hope, believe me Useful tips on living with MS Where are my injection sites? How do I use the injection schedule? Physiotherapy & Me Keeping track with your treatment